Throughout this application various publications are referred to by Arabic numerals in superscript. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications are hereby incorporated by reference in their entireties into the subject application to more fully describe the art to which the subject application pertains.
Mitochondria are organelles that influence nearly every important cellular process including metabolism, transcription and translation, survival, growth and differentiation. Regulation of these processes is beneficial in a variety of pathological states in which mitochondria contribute to the pathogenesis or maintenance of a disease. This includes those that may have multi-factorial etiologies such as cancer or aging.
Magmas (Mitochondria associated granulocyte-macrophage colony stimulating factor signaling molecule), a granulocyte-macrophage colony stimulating factor (GM-CSF) inducible gene, has been identified in myeloid cells1. Magmas mRNA expression was observed in all tissues examined1. Magmas protein localizes to the inner membrane of mitochondria, and protein expression is both developmentally regulated and tissue specific2. The protein is highly conserved, and is required for mitochondria function and cell survival3. Immuno-precipitation and immuno-affinity chromatography studies show that Magmas mostly interacts with other mitochondrial proteins. Impairment of Magmas function differentially affects complex IV activity, leading to loss of mitochondrial membrane potential.
Magmas expression in prostate cancer samples suggested a role for this protein in human cancer4. Magmas staining is minimal to absent in normal prostate tissue by immuno-histochemistry. Elevated levels of Magmas protein occurred in a subset of advanced-grade, invasive adenocarcinoma. However, many samples of similar stage had staining patterns identical to normal prostate epithelium. Increased staining resulted from higher amounts of Magmas in the abnormal cells and not from increased numbers of mitochondria. Since not all patients with morphological high-grade prostate cancer do poorly, one possibility is that Magmas expression may affect therapeutic response to therapy, possibly by altering mitochondrial function. Data from independent laboratories showing that Magmas mRNA expression correlates with survival in several human tumors (breast,10,11 colon and lung) is consistent with this theory.
Based on the discovery of Magmas and its role in mitochondrial activity, there is a pressing need for compounds capable of manipulating such activity by inhibiting Magmas in cells. The present invention addresses this need.